Spilanthol has been reported to possess antioxidant, anti‑inflammatory, antimicrobial and antinociceptive properties. At present, the literature has reported the beneficial role of spilanthol on tumor necrosis factor‑α (TNF‑α)‑stimulated HaCaT cells. The present study investigated the effects of spilanthol on the expression of TNF‑α‑induced intercellular adhesion molecule 1 (ICAM‑1) and cyclooxygenase (COX)‑2 in the human keratinocyte cell line HaCaT. Cells were pretreated with various concentrations of spilanthol (10‑150 µM) followed by TNF‑α to induce inflammation. Pretreatment with spilanthol decreased TNF‑α‑induced COX‑2 expression by western blotting and suppressed the expression of pro‑inflammatory mediators, including interleukin (IL)‑6, IL‑8 and monocyte chemotactic protein 1 using ELISA. Spilanthol also decreased the expression of TNF‑α‑induced ICAM‑1 protein and mRNA assay by western blotting and RT‑qPCR, respectively, in addition to the monocyte adhesiveness of HaCaT cells. Furthermore, spilanthol significantly suppressed the phosphorylation of c‑Jun N‑terminal kinase (JNK), while pretreatment with spilanthol enhanced heme oxygenase (HO)‑1 protein expression by western blotting. These results demonstrated that spilanthol may exert its anti‑inflammatory activity by suppressing the TNF‑α‑induced expression of ICAM‑1, COX‑2 and pro‑inflammatory mediators by enhancing that of HO‑1, and inhibiting the activation of the phosphorylated JNK signaling pathway. It is hypothesized that spilanthol may be a natural anti‑inflammatory drug to attenuate skin inflammatory disease.